Pharmaceutical combinations comprising salmeterol and fluticasone proprionate for the treatment of asthma

ABSTRACT

Methods for the prophylaxis or treatment of asthma by once daily administration of salmeterol and fluticasone propionate combinations as well as suitable pharmaceutical formulations are disclosed.

The present invention relates to the use of salmeterol and fluticasonepropionate combinations for the once daily treatment of respiratorydisorders, in particular asthma.

The combination of the beta-2 adrenergic agonist salmeterol or aphysiologically acceptable salt thereof and the corticosteroidfluticasone propionate has been described in GB 2 235 627 for use in thetreatment of asthma and other respiratory disorder via a twice daily(bis in diem—b.i.d) dosing regimen. The combination of salmeterolxinafoate and fluticasone propionate is now used clinically in thetreatment of asthma. It is indicated for b.i.d. dosing.

Fluticasone propionate is an anti-inflammatory corticosteroid, describedin GB 2088877, and is systematically namedS-fluoromethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate.Fluticasone propionate is now used clinically for the treatment ofbronchial asthma and related disorders. Fluticasone propionate isindicated for b.i.d. dosing for the maintenance treatment of asthma.

GB 2 140 800 describes phenethanolamine compounds which areβ₂-adrenoreceptor agonists including4-hydroxy-α^(†)-[[[6-(4-phenylbutoxy)hexyl]-amino]methyl]-1,3-benzenedimethanol1-hydroxy-2-naphthalenecarboxylate (salmeterol xinafoate) which is nowused clinically in the treatment of bronchial asthma and relateddisorders. Salmeterol is now used clinically for the treatment ofbronchial asthma and related disorders. It is indicated for b.i.d.dosing.

Asthma is a condition characterised by variable, reversible obstructionof the airways which is caused by a complex inflammatory process withinthe lungs. In most cases, this process is initiated and maintained bythe inhalation of antigens by sensitive atopic individuals (extrinsicasthma). However, in some patients it is caused by other mechanismswhich at present are poorly understood but do not involve an allergicprocess (intrinsic asthma). The disease has therefore two components,spasm of the bronchial (or breathing) tubes and inflammation or swellingof the breathing tubes.

Selective β₂-adrenoceptor agonists such as salbutamol have been usedsuccessfully and effectively by inhalation for the immediate relief ofspasm in asthma. Salmeterol has a prolonged duration of action (“longacting”) of selective β₂-adrenoceptor antagonism enabling longer termcontrol of bronchospasm and in reflection of this is included as a“controller medication” in international treatment guidelines such asGINA (Global Initiative For Asthma), (NHLBI/WHO Workshop Report,National Institutes of Health, National Heart Lung and Blood Institute,NIH Publication No. 95-3659, January 1995, and A Practical Guide forPublic Health Care Professionals, National Institutes of Health,National Heart Lung and Blood Institute, NIH Publication No. 95-3659A,December 1995).

Anti-inflammatory corticosteroids such as, for example, fluticasonepropionate have also been administered by inhalation in the treatment ofasthma, although unlike β₂-adrenoceptor agonists the therapeuticbenefits resulting from reduced inflammation may not be immediatelyapparent.

Fluticasone propionate, salmeterol xinafoate, and combinations ofsalmeterol xinafoate and fluticasone propionate, have previously onlybeen proposed for the treatment or prophylaxis of asthma on the basis ofa twice daily dose regimen. We have now surprisingly found that, in somepatient populations, asthma can be satisfactorily controlled by the useof a combination of salmeterol or a physiologically acceptable saltthereof and fluticasone propionate on a once daily basis.

Accordingly, the present invention provides a method for prophylaxis ortreatment of asthma in a mammal, such as a human, which comprisesadministering an effective amount of a combination of salmeterol or aphysiologically acceptable salt thereof, such as the xinafoate salt, andfluticasone propionate on a once daily basis. In particular, there isprovided a method for prophylaxis or treatment of mild or moderateasthma, especially persistent asthma, in a mammal, such as a human,which comprises administering an effective amount of a combination ofsalmeterol or a physiologically acceptable salt thereof, such as thexinafoate salt, and fluticasone propionate on a once daily basis.

In the alternative, there is provided the use of a combination ofsalmeterol or a physiologically acceptable salt thereof, such as thexinafoate salt, and fluticasone propionate for the manufacture of amedicament for the prophylaxis or treatment of asthma on a once dailybasis. In particular, there is provided the use of a combination ofsalmeterol or a physiologically acceptable salt thereof, such as thexinafoate salt, and fluticasone propionate for the manufacture of amedicament for the prophylaxis or treatment of mild or moderate asthma,especially persistent asthma, on a once daily basis.

The severity of a patient's asthma can be classified as mild, moderateor severe depending on various criteria such as pulmonary function,symptamatology and the medication required in order to achieve effectivecontrol of the disease. Once daily dosing with a combination ofsalmeterol or a physiologically acceptable salt thereof, such as thexinafoate salt, and fluticasone propionate is particularly suitable forthe treatment or prophylaxis of mild or moderate asthma, especiallypersistent asthma. Treatment may be initiated on the basis of once dailydosing, or may be stepped down from b.i.d. dosing to once daily dosingonce a patient's asthma has stabilised. Once asthma stability for apatient has been achieved, it is desirable to titrate to the lowesteffective dose to reduce the possibility of any potential side effects.Once daily dosing also allows greater flexibility to physicians inprescribing treatment for persistent asthma.

The need for a b.i.d. dosing regimen may discourage effective patientcompliance. Once daily dosing offers a more convenient dosing regimenfor patients and may lead to improved patient compliance with the dosingregimen. This can be especially important for paediatric patients.

As used herein, the term “treatment” means the improvement of clinicaloutcome, for example, alleviation of the symptoms of asthma, includingnocturnal asthma, in particular prevention of bronchospasm, nocturnalcough, breathlessness and wheeze, and improvement in daytime lungfunction.

As used herein, the term “once daily” means that a patient's asthma isadequately controlled when the patient takes an effective dose of thecombination of salmeterol or a physiologically acceptable salt thereof,such as the xinafoate salt, and fluticasone propionate onceapproximately every 24 hours. Preferably, a patient will take aneffective dose of the combination at the same time in each 24 hourperiod, for example every morning, every afternoon or every evening,such that the individual doses are approximately 24 hours apart.

Throughout the specification and the claims which follow, unless thecontext requires otherwise, the word ‘comprise’, and variations such as‘comprises’ and ‘comprising’, will be understood to imply the inclusionof a stated integer or step or group of integers but not to theexclusion of any other integer or step or group of integers or steps.

It will be appreciated that the compounds of the salmeterol andfluticasone propionate combination may be administered simultaneously,either in the same or different pharmaceutical formulations, orsequentially. Where there is sequential administration, the delay inadministering the second and any subsequent active ingredient should notbe such as to lose the beneficial therapeutic effect of the combinationof the active ingredients. In a preferred aspect of the invention, thesalmeterol or its physiologically acceptable salt and the fluticasonepropionate are administered as a combined pharmaceutical formulation.The weight/weight ratio of salmeterol to fluticasone administeredaccording to the invention is preferably in the range 4:1 to 1:20.

The amount of salmeterol or a physiologically acceptable salt thereof,such as the xinafoate salt, and fluticasone propionate which is requiredto achieve a therapeutic effect will, of course, vary with theparticular salt form, the route of administration, the subject undertreatment, and the particular disorder or disease being treated. Thecombination of the invention may be administered to an adult human byinhalation at a dose of from 50 μg to 2000 μg per day, suitably 50 μg to500 μg per day, more suitably 100 μg to 400 μg per day of fluticasonepropionate and 50 μg to 200 μg per day, suitably 50 μg to 100 μg per dayof salmeterol. The combination of the invention are preferablyadministered to an adult human by inhalation at a dose 50 μg ofsalmeterol, optionally in the form of the xinafoate salt, and 50 μg, 100μg, 250 μg or 500 μg of fluticasone propionate per day, particularlypreferably 50 μg of salmeterol, optionally in the form of the xinafoatesalt, and 250 μg of fluticasone propionate per day.

The total daily dose may be inhaled in one actuation of an inhaler, forexample a dry powder inhaler or a metered dose inhaler, or in more thanone actuation, for example in 2, 3, or 4 actuations or “puffs”.

While it is possible for salmeterol or a physiologically acceptable saltthereof, such as the xinafoate salt, and fluticasone propionate to beadministered as raw drugs, it is preferable to present each of them as apharmaceutical formulation.

Thus according to a further aspect of the invention, there is provided apharmaceutical formulation for the prophylaxis or treatment of asthma ona once daily basis comprising salmeterol or a physiologically acceptablesalt thereof, such as the xinafoate salt, and fluticasone propionate,and a pharmaceutically acceptable carrier or excipient, and optionallyone or more other therapeutic agents. Preferably, the pharmaceuticalformulation is in a form which is suitable for administration byinhalation.

Hereinafter, the term “active ingredient” means salmeterol or aphysiologically acceptable salt thereof, such as the xinafoate salt,and/or fluticasone propionate.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous andintraarticular), inhalation (including fine particle dusts or mistswhich may be generated by means of various types of metered dosepressurised aerosols, nebulisers or insufflators), rectal and topical(including dermal, buccal, sublingual and intraocular) administrationalthough the most suitable route may depend upon for example thecondition and disorder of the recipient. The formulations mayconveniently be presented in unit dosage form and may be prepared by anyof the methods well known in the art of pharmacy. All methods includethe step of bringing the active ingredients into association with thecarrier which constitutes one or more accessory ingredients. In generalthe formulations are prepared by uniformly and intimately bringing intoassociation the active ingredients with liquid carriers or finelydivided solid carriers or both and then, if necessary, shaping theproduct into the desired formulation.

Formulations for inhalation include powder compositions which willpreferably contain lactose, and spray compositions which may beformulated, for example, as aqueous solutions or suspensions or asaerosols delivered from pressurised packs, with the use of a suitablepropellant, e.g. dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane,1,1,1,2-tetrafluoroethane, carbon dioxide or other suitable gas.Suitable aerosol formulations include those described in EP 0372777 andWO93/11743. For suspension aerosols, the active ingredients should bemicronised so as to permit inhalation of substantially all of the activeingredients into the lungs upon administration of the aerosolformulation, thus the active ingredients will have a particle size ofless than 100 microns, desirably less than 20 microns, and preferably inthe range 1 to 10 microns, for example, 1 to 5 microns.

Intranasal sprays may be formulated with aqueous or non-aqueous vehicleswith the addition of agents such as thickening agents, buffer salts oracid or alkali to adjust the pH, isotonicity adjusting agents oranti-oxidants.

Capsules and cartridges or for example gelatin, or blisters of forexample laminated aluminium foil, for use in an inhaler or insuflatormay be formulated containing a powder mix of the active ingredients anda suitable powder base such as lactose or starch. In this aspect, theactive ingredients are suitably micronised so as to permit inhalation ofsubstantially all of the active ingredients into the lungs uponadministration of the dry powder formulation, thus the activeingredients will have a particle size of less than 100 microns,desirably less than 20 microns, and preferably in the range 1 to 10microns.

Solutions for inhalation by nebulation may be formulated with an aqueousvehicle with the addition of agents such as acid or alkali, buffersalts, isotonicity adjusting agents or antimicrobials. They may besterilised by filtration or heating in an autoclave, or presented as anon-sterile product.

Preferred unit dosage formulations are those containing apharmaceutically effective dose, as hereinbefore recited, or anappropriate fraction thereof, of the active ingredient. Thus, in thecase of formulations designed for delivery by metered dose pressurisedaerosols, one actuation of the aerosol may deliver half of thetherapeutically effective amount such that two actuations are necessaryto deliver the therapeutically effective dose.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations used according to the invention mayinclude other agents conventional in the art having regard to the typeof formulation in question, for example those suitable for oraladministration may include flavouring agents. Furthermore, the claimedformulations include bioequivalents as defined by the US Food and DrugsAgency.

Furthermore, the combination of salmeterol or a physiologicallyacceptable salt hereof, such as the xinafoate salt, and fluticasonepropionate used according to the present invention may be used incombination with or include a further active ingredient, for exampleanti-inflammatory agents (such as other corticosteroids (e.g.beclomethasone dipropionate, mometasone furoate, triamcinolone acetonideor budesonide) or NSAIDs (e.g. sodium cromoglycate, nedocromil sodium,PDE4 inhibitors, leukotriene antagonists, iNOS inhibitors, tryptase andelastase inhibitors, beta-2 integrin antagonists and adenosine 2aagonists)) or other β2-adrenoreceptor agonists (such as salbutamol,formoterol, fenoterol or terbutaline and salts thereof), anticholinergicagents (such as ipratropium, oxitropium or tiotropium) or antiinfectiveagents (e.g. antibiotics, antivirals).

For a better understanding of the invention, the following Examples aregiven by way of illustration.

EXAMPLES Example 1 25/50 Salmeterol/Fluticasone Propionate Metered DoseInhaler

Per actuation Salmeterol Xinafoate 36.3 microgram Fluticasone Propionate  50 microgram 1,1,1,2-Tetrafluoroethane to 75.0 mg

The micronised active ingredients are weighed into an aluminium can,1,1,1,2-tetrafluoroethane is then added from a vacuum flask and ametering valve is crimped into place.

Similar methods may be used for the formulation of Examples 2 to 4:

Example 2 25/125 Salmeterol/Fluticasone Propionate Metered Dose Inhaler

Per actuation Salmeterol Xinafoate 36.3 microgram Fluticasone Propionate 125 microgram 1,1,1,2-Tetrafluoroethane to 75.0 mg

Example 3 25/250 Salmeterol/Fluticasone Propionate Metered Dose Inhaler

Per actuation Salmeterol Xinafoate 36.3 microgram Fluticasone Propionate 250 microgram 1,1,1,2-Tetrafluoroethane to 75.0 mg

Example 4 25/500 Salmeterol/Fluticasone Propionate Metered Dose Inhaler

Per actuation Salmeterol Xinafoate 36.3 microgram Fluticasone Propionate 500 microgram 1,1,1,2-Tetrafluoroethane to 75.0 mg

Example 5 50/50 Salmeterol/Fluticasone Propionate Dry Powder Inhaler

Per cartridge or blister Salmeterol Xinafoate 72.5 microgram FluticasonePropionate   50 microgram Lactose Ph.Eur. to 12 mg or to 25 mg

The active ingredients are micronised and bulk blended with the lactosein the proportions given above. The blend is filled into hard gelatincapsules or cartridges or in specifically constructed double foilblister packs (Rotadisks blister packs, Glaxo Group trade mark) to beadministered by an inhaler such as the Rotahaler inhaler (Glaxo Group,trade mark) or in the case of the blister packs with the Diskhaler orDiskus inhalers (Glaxo Group trade marks).

Similar methods may be used for the formulation of Examples 6 to 8:

Example 6 50/100 Salmeterol/Fluticasone Propionate Dry Powder Inhaler

Per cartridge or blister Salmeterol Xinafoate 72.5 microgram FluticasonePropionate  100 microgram Lactose Ph.Eur. to 12 mg or to 25 mg

Example 7 50/100 Salmeterol/Fluticasone Propionate Dry Powder Inhaler

Per cartridge or blister Salmeterol Xinafoate 72.5 microgram FluticasonePropionate  250 microgram Lactose Ph.Eur. to 12 mg or to 25 mg

Example 8 50/100 Salmeterol/Fluticasone Propionate Dry Powder Inhaler

Per cartridge or blister Salmeterol Xinafoate 72.5 microgram FluticasonePropionate  500 microgram Lactose Ph.Eur. to 12 mg or to 25 mg

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, method, or use claims and may include, by way ofexample and without limitation, the following claims:

1. A method for prophylaxis or treatment of asthma in a mammal, which comprises administering an effective amount of a combination of salmeterol or a physiologically acceptable salt thereof and fluticasone propionate on a once daily basis.
 2. A method according to claim 1 wherein the salmeterol or physiologically acceptable salt thereof and fluticasone propionate are administered as a combined pharmaceutical formulation.
 3. A method according to claim 1 in which the salmeterol or physiologically acceptable salt thereof and fluticasone propionate are administered by inhalation.
 4. A method according to claim 1 in which the salmeterol is administered as the xinafoate salt. 5-13. (Canceled).
 14. A method according to claim 2 in which the salmeterol or physiologically acceptable salt thereof and fluticasone propionate are administered by inhalation.
 15. A method according to claim 2 in which the salmeterol is administered as the xinafoate salt.
 16. A method according to claim 3 in which the salmeterol is administered as the xinafoate salt.
 17. A method according to claim 14 in which the salmeterol is administered as the xinafoate salt.
 18. A method according to claim 1 in which the effective amount is from 50 μg to 2000 μg per day fluticasone propionate and 50 μg to 200 μg per day salmeterol.
 19. A method according to claim 1 in which the effective amount is from 100 μg to 400 μg per day fluticasone propionate and 50 μg to 200 μg per day salmeterol.
 20. A method according to claim 1 in which the effective amount is from 100 μg to 400 μg per day fluticasone propionate and 50 μg to 100 μg per day salmeterol.
 21. A method according to claim 3 in which the daily dose is inhaled in one actuation of an inhaler.
 22. A method according to claim 14 in which the daily dose is inhaled in one actuation of an inhaler.
 23. A method for prophylaxis or treatment of asthma in a human which comprises administering an effective amount of a combination of salmeterol or a physiologically acceptable salt thereof and fluticasone propionate on a once daily basis, wherein the salmeterol or physiologically acceptable salt thereof and fluticasone propionate are administered by inhalation as a combined pharmaceutical formulation in which the effective amount is from 100 μg to 400 μg per day fluticasone propionate and 50 μg to 100 μg per day salmeterol.
 24. A method according to claim 23 in which the daily dose is inhaled in one actuation of an inhaler.
 25. A method according to claim 23 in which the effective amount is administered by inhalation from a powdered dose inhaler.
 26. A method according to claim 23 in which the effective amount is administered by inhalation from a metered dose inhaler.
 27. A method for prophylaxis or treatment of asthma in a human which comprises administering an effective amount of a combination of salmeterol or a physiologically acceptable salt thereof and fluticasone propionate on a once daily basis, wherein the salmeterol or physiologically acceptable salt thereof and fluticasone propionate are administered by inhalation as a combined pharmaceutical formulation and in which the daily dose is inhaled in one actuation of an inhaler.
 28. A method according to claim 27 in which the effective amount is administered by inhalation from a powdered dose inhaler.
 29. A method according to claim 27 in which the effective amount is administered by inhalation from a metered dose inhaler. 